Inhibition of methionine biosynthesis eliminates persistent M. tuberculosis.

抑制蛋氨酸生物合成可以消除持续存在的结核分枝杆菌。

• 批准号: 9214311
• 负责人: Michael Berney
• 金额: $ 20.88万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9214311
• 关键词: Acute; Address; Amino Acids; Anabolism; Antibiotics; Appearance; Bacillus (bacterium); Bacteria; Biomedical Research; California; Cell Death; Cell physiology; Cells; Chemicals; Chronic; Collaborations; Complement; Data; Drug Targeting; Drug resistance; Essential Amino Acids; Extreme drug resistant tuberculosis; Failure; Future; Gene Silencing; Goals; Grant; Human; Immunocompetent; Immunocompromised Host; In Vitro; Infection; Institutes; Luciferases; Mammals; Metabolic; Metabolic Pathway; Methionine; Methyltransferase; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; Outcome; Pharmaceutical Preparations; Phase; Population; Preclinical Drug Evaluation; Probability; Proliferating; Publications; Publishing; Relapse; Reporter; Research; Research Institute; S-Adenosylmethionine; Seizures; Serum; Starvation; Sterilization; Supplementation; System; Time; Tissues; Tuberculosis; Validation; Virulence; aminoacid biosynthesis; base; cell envelope; chemotherapy; drug development; drug discovery; experimental study; extensive drug resistance; in vivo; inhibitor/antagonist; interdisciplinary approach; killings; macrophage; metabolomics; microbicide; mutant; new therapeutic target; novel; novel therapeutics; pathogen; protein degradation; public health relevance; screening; small molecule inhibitor; tool; transcriptomics; tuberculosis drugs

 DESCRIPTION (provided by applicant): Mycobacterium tuberculosis is the most deadly bacterial pathogen in the world, killing 1.2 million people yearly and infecting over 8 million (WHO, 2013). Although chemotherapy against TB exists, a rapid global increase of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) cases makes new drugs with novel killing mechanisms an urgent need. A major drawback of current TB chemotherapy is its long duration, which increases the probability of relapse and the emergence of drug resistance. The underlying problem of this phenomenon is a population of non-replicating, drug-tolerant bacilli, the so-called persisters. However, current TB drugs are mainly effective against replicating and metabolically active bacteria. Preferably, new drugs kill fast (within weeks) and target actively growing as well as persister cells. Using a multidisciplinary approach, we have identified a novel drug target in methionine biosynthesis of M. tuberculosis. Our preliminary results are very promising, as they show rapid in vitro sterilization of a M. tuberculosis methionine auxotroph as well as complete lack of virulence in immunocompetent and immunocompromised mice. This is intriguing because most available TB antibiotics do not rapidly sterilize cultures. Metabolomics and transcriptomic analysis revealed a systemic metabolic shutdown by an unprecedented multi-target inhibition mechanism. The prospect of killing M. tuberculosis by causing rapid biosynthetic and metabolic seizure is very attractive for drug discovery. The goal of this proposal is to validate this drug target in vitro and in vivo and o develop a reporter strain for whole cell inhibitor screening. This will set the stage for a comprehensive high-throughput inhibitor screen against this target in the near future.

 描述（由申请人提供）：结核分枝杆菌是世界上最致命的细菌病原体，每年夺去 120 万人的生命，感染超过 800 万人（世界卫生组织，2013 年）。 MDR）和普遍耐药（XDR）结核病（TB）病例使得迫切需要具有新颖杀伤机制的新​​药，目前结核病化疗的一个主要缺点是。其持续时间长，增加了复发的可能性和出现耐药性，这种现象的根本问题是非复制的耐药杆菌，即所谓的持久性杆菌，但目前的结核病药物主要是有效的。优选地，新药物能够快速杀死（几周内）并靶向活跃生长的细胞和持久细胞，利用多学科方法，我们已经确定了支原体甲硫氨酸生物合成的新药物靶标。我们的初步结果非常有希望，因为它们显示了结核分枝杆菌蛋氨酸营养缺陷型的快速体外灭菌，并且在免疫功能正常和免疫功能低下的小鼠中完全缺乏毒力，这很有趣，因为大多数可用的结核病抗生素不能快速灭菌培养物。代谢组学和转录组学分析揭示了前所未有的多靶点抑制机制导致的系统代谢关闭，从而导致快速杀死结核分枝杆菌。生物合成和代谢捕获对于药物发现非常有吸引力，该提案的目标是在体外和体内验证该药物靶标，并开发用于全细胞抑制剂筛选的报告菌株。在不久的将来针对该目标进行抑制剂筛选。